1) Field of the Invention
This invention relates to a total synthetic process for producing the macrolide immunosuppressant FK-506 and important tricarbonyl process intermediates thereof.
2) Brief Disclosures in the Art
The novel 23-membered tricyclo-macrolide FK-506 isolated and characterized by Tanaka, Kuroda, and co-workers, see JACS, 109, pp. 5031, 1987, and EPO Publication No. 0,184,162, has been shown to possess exceptional immunosuppressive activity. The potential usefulness of such an agent in bone marrow and organ transplantations coupled with its unique structural features has prompted many in the field to initiate an effort towards the total synthesis of FK-506 (1). ##STR1##
A formidable problem in the general and specific solution to the synthesis of FK-506, is the formation of the tricarbonyl lactol moiety of FK-506, (the C.sub.8 -C.sub.9 -C.sub.10 tricarbonyl moiety in lactol form) particularly in the presence of olefin moieties. For example, there are no examples for the preparation of 2,3-diketo carboxylates, carboxamides, carboxamides, or their corresponding lactol derivatives by the oxidation of 2,3-dihydroxy carboxylates and concomitant lactolization in a macrolide molecule also possessing an olefin moiety (for a review on the preparation of the tricarbonyl functionality see M. B. Rubin, Chemical Reviews, 75, 177, 1975, and references therein).
Prior preparations of the 2,3-diketocarboxyl functionality have involved either oxidation of beta-keto esters (H. H. Wasserman, W. T. Han, Tetrahedron Letters, 25, 3743, 1984; or Williams, D. R., Benbow, J. W., J. Org. Chem., 1988, 53, 4643) or the acylation of oxalate anion equivalents, e.g. 1,2-diethoxy-1,2-bis-(trimethylsilyloxy) ethylene with an appropriate electrophile such as an acid chloride or an active ester derivative thereof (see M. T. Reetz, S. H. Kyung, Tetrahedron Letters, 26, 6333, 1985).
These procedures would be inapplicable for the FK-506 system due to the harshness of the reaction conditions in each approach. The oxidation of beta-ketoesters to 2,3-diketoesters would not be compatible with the olefinic linkages present in FK-506 systems because they would also be susceptible to oxidation. Similarly, the strong Lewis acid conditions necessary for the addition of oxalate equivalents to acid chlorides as used in the Reetz approach would not be applicable in the presence of the many sensitive hydroxyl or protected hydroxyl functional groups of FK-506.
What is needed in the art is an overall general synthesis for FK-506 utilizing readily available starting materials which would allow the synthesis of the tricarbonyl moiety of FK-506 in the presence of olefin functionality.